Effects of age and gender on reference levels of biomarkers comprising the pediatric Renal Activity Index for Lupus Nephritis (p-RAIL)

Abstract

BackgroundSystemic Lupus Erythematosus (SLE) is a multisystem autoimmune disease that disproportionately effects women and children of minorities. Renal involvement (lupus nephritis, or LN) occurs in up to 80% of children with SLE and is a major determinant of poor prognosis. We have developed a non-invasive pediatric Renal Activity Index for Lupus (p-RAIL) that consists of laboratory measures that reflect histologic LN activity. These markers are neutrophil gelatinase associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), monocyte chemotactic protein (MCP-1), adiponectin (APN), ceruloplasmin (CP) and hemopexin (HPX). A major gap in the knowledge base and a barrier to clinical utility is how these markers behave in healthy children. We set out to establish a reference range for the p-RAIL markers in a population of healthy children, and to determine if levels of these markers fluctuate with age or gender.MethodsUrine was collected from 368 healthy children presenting to Cincinnati Children’s primary care clinic for well child visits and assayed for NGAL, KIM-1, MCP-1, APN, CP and HPX using commercially available kits or assay materials.ResultsSpecimens were grouped by age (0–5 years (n = 94); 5–10 (n = 89); 10–15 (n = 93); 15–20 (n = 91)) and gender (M = 184, F = 184). For age and gender comparisons, values were log transformed prior to analysis. The medians (minimums, maximums) of each marker in the combined population were as follows: NGAL 6.65 (0.004, 391.52) ng/ml, KIM-1416.84 (6.22, 2512.43) pg/ml, MCP-1209.36 (9.49, 2237.06) pg/ml, APN 8.05 (0.07, 124.50) ng/ml, CP 465.15 (8.02, 7827.00) ng/ml, HPX 588.70 (6.85, 17,658.40)ng/ml. All p-RAIL biomarkers but adiponectin had weak but significant positive correlations with age, with NGAL being the strongest (r = 0.33, p < 0.001). For gender comparisons, NGAL, CP and HPX were elevated in females vs males (86%, p < 0.0001; 3%, p = 0.007, and 5%, p = 0.0005 elevation of the log transformed mean, respectively).ConclusionsWe have established a reference range for the p-RAIL biomarkers and have highlighted age and gender differences. This information is essential for rational interpretation of studies and clinical trials utilizing the p-RAIL algorithm.

Age‐Dependent Changes of Kidney Injury Biomarkers in Pediatrics

“…KI biomarker values in the healthy pediatric population . Left and right panels illustrate biomarker values retrieved from urine and serum, respectively.…”

“…It provides the estimated glomerular filtration rate and is based on the child's height and values of serum creatinine, a by‐product of muscle metabolism eliminated through glomerular filtration . Unfortunately, estimated glomerular filtration rate and serum creatinine are both unreliable and inaccurate markers for monitoring of kidney function and detecting KI in pediatric populations for the following reasons: (1) approximately 50% of renal parenchymal loss must occur before serum creatinine changes can be detected; (2) serum creatinine can be influenced by muscle mass variation, nutrition, age, and sex; (3) during the first days of life, serum creatinine rather reflects the maternal kidney function instead of the kidney function of the neonate; (4) overestimation of kidney function is possible in patients with cachexia; and (5) serum creatinine does not allow the exact localization nor the extent of KI …”

“…37 In summary, when urinary NGAL values are combined for 4 different age groupspreterm neonates (<37 weeks' gestational age and <1 month), term neonates (>37 weeks' gestational age and <1 month), infants (>1 month and <3 years), and children (>3 and <20 years)-a decrease in urinary NGAL values can be observed from prematurity to childhood, which illustrates the age dependency of this KI biomarker (Figure 3). 18,20,23,29,30,[32][33][34]37 Left and right panels illustrate biomarker values retrieved from urine and serum, respectively. Standard deviation, interquartile range, and confidence intervals are represented by dashed, dotted, or full lines, respectively.…”

“…10 Unfortunately, estimated glomerular filtration rate and serum creatinine are both unreliable and inaccurate markers for monitoring of kidney function and detecting KI in pediatric populations for the following reasons: (1) approximately 50% of renal parenchymal loss must occur before serum creatinine changes can be detected; (2) serum creatinine can be influenced by muscle mass variation, nutrition, age, and sex; (3) during the first days of life, serum creatinine rather reflects the maternal kidney function instead of the kidney function of the neonate; (4) overestimation of kidney function is possible in patients with cachexia; and (5) serum creatinine does not allow the exact localization nor the extent of KI. [11][12][13][14][15][16][17][18][19][20][21][22][23] Understanding Age-Dependent Changes in Pediatrics Kidney function comprises 3 main processes: First, glomerular filtration is responsible for the filtration of the plasma across the glomerular membrane into the renal tubule. Second, tubular excretion transporters can increase the excretion of drug molecules by more actively transport from the plasma into the tubule.…”

Urine biomarkers of chronic kidney damage and renal functional decline in childhood-onset systemic lupus erythematosus

“…Urine creatinine and urine albumin were reported as mg/ dL and mg/L, respectively. Normal ranges for these biomarkers have been established [35]. …”